The identity and function of regulated blood-brain barrier transporters (BBB) for essential nutrients and drugs were examined in relation to aging and disease. Two basic amino acid transporters (CAT-1 and CAT-2) were identified at the BBB by mRNA analysis, as well as a putative accessory or modulatory subunit (4F2). CAT-1 transporter expression was shown to decrease with age after birth, concomitant with the developmental decline in brain protein synthesis and growth rate. The substrate selectivity of the choline and neutral amino acid transporters were examined and high affinity ligands for each transporter were identified. On the basis of structure/activity studies, new drugs were developed that showed enhanced uptake into brain via carrier-mediated transport. One such compound, D,L-NAM, exhibited 20-40 fold greater brain uptake than its clinical analog, L-melphalan, and was further developed for brain antitumor testing. A similar compound, 4-chloro-kynurenine, was examined as a neuroprotective agent against excitotoxic brain damage. Computer models of the binding sites of the BBB choline and neutral amino acid transporters were developed to aid in the design of new drugs that are selectively shuttled into brain by the transport mechanisms.